4.2 - Iron Metabolism And Microcytic Anaemias Flashcards
What is alpha thalassaemia?
Deletion or loss of function of one or more of the four alpha globin genes
What is b thalassaemia?
Mutation in b globin genes leading a reduction or absence of the b globin.
What are the causes of microcytic anaemia?
Thalassaemia trait Anaemia of chronic disease Iron deficiency Lead poisoning Sideroblastic anaemia
TAILS
What are the two forms of iron and what is the difference?
Ferrous (Fe2+)= reduced form, and ferric (Fe3+) oxidised form
Ferrous is acidic
Ferric is alkaline
Ferric iron must be reduced to ferrous to be absorbed from diet
Where is iron absorbed?
Duodenum and upper jejunum
How is dietary iron absorbed?
1) reductase transforms ferric iron to ferrous with help from vit c
2) enters cell with DMT1 receptor
3) either stored in cell or combined with haem using haemoxygenae
4) leaves cell to go into blood stream via ferroportin using hepcindin (made by liver) which changes the shape of receptor
5) converted back to ferric iron by Hephaestin and binds to transferrin to go around the body.
What are negative influences of absorption of non haem iron from food?
Negative
- tannins in tea
- phytates (chapattis)
- fibres
- antacids
What are the positive influences of absorption of non haem iron from food?
Vitamin c and citrate
- prevent formation of insoluble iron compounds
- vit c also helps reduce ferric to ferrous iron
What is stored iron?
Ferritin - soluble
- globular protein complex with hollow core
- pores allow iron to enter and be released
Haemosiderin - insoluble
- aggregates of clumped ferritin particles, denatured protein and lipid
- accumulates in macrophages, particularly in liver, spleen and marrow
What is functional iron?
- haemoglobin
- myoglobin
- enzymes
- transported iron (in serum, mainly transferrin)
How is iron taken up by a cell?
1) fe3+ bound transferrin binds transferrin receptor and enters the cytosol receptor mediated endocytosis
2) fe3+ within endosome released by acidic microenvironment and reduced to fe2+
3) the fe2+ transported to the cytosol via DMT1
4) Once in the cytosol, fe2+ can be stored in ferritin, exported by ferroportin or taken up by mitochondria for use in cytochrome enzymes
Where can recycled iron come from?
- damaged RBC
- engulfed by macrophages, mainly splenic or kupffer cells of liver
- catabolise haem released by RBC
- iron stored as ferritin in macrophage
What are the control mechanisms of iron absorption?
- regulation of transporters e.g ferroportin
- regulation of receptors e.g transferrin receptor and HFE protein (interacts with receptor)
- hepcidin and cytokines
- crosstalk between epithelial cells and other cells like macrophages
What does hepcidin do?
Made by liver, a key negative regulator of iron absorption
- induced internalisation and degradation of ferroportin = iron cant leave cell, whether it be an enterocyte or a macrophage storing recycled iron
It’s synthesis is increased in iron overload and decreased by high erythropoetic activity.
How can iron deficiency anaemias result from chronic disease?
1) Inflammatory condition
2) cytokines released by immune cells (= inhibition of erythropoietin production by kidneys = less erythropoiesis)
OR
3) increased production of hepcidin by liver = inhibition of ferroportin
4) decreased iron released from RES and less abortion in the gut = inhibition of erythropoiesis in bone marrow
= ANAEMIA OF CHRONIC DISEASE
What are the causes of iron deficiency?
- insufficient diet
- menstrual bleeding
- malabsorption of iron
- increased requirement e.g pregnancy
- anaemia of chronic disease e.g inflammatory bowel disease
What are the physiological effects of anaemia?
- tired
- pallor
- tachycardia
- angina, palpitations, development of heart failure
- increased respiratory rate
- dizziness
- cold hands and feet
What do you expect in the FBC with iron defiance anaemia?
- low mean corpuscular volume
- low mean corpuscular haemoglobin conc
- elevated platelet count
- normal or elevated wbc count
- low serum ferritin and iron
What would you expect in a blood smear of someone with iron deficiency anaemia?
- RBC are microcytic and hypochromic in chronic cases
- different sizes and shapes
- sometime pencil cells and target cells.
What does reduced plasma ferritin indicate?
Iron deficiency indefinetively
Where would ferritin levels increase?
Cancer Infection Inflammation Liver disease Alcoholism Or iron deficiency but more likely reduced
How do you treat iron deficiency?
- diet
- oral iron supplements
- intramuscular iron injections
- intravenous iron
- blood transfusion (only if severe)
Why is excess iron dangerous?
Excess iron can exceed binding capacity of transferrin so is deposited in organs as haemosiderin. Iron promotes free radical formation and organ damage e.g cirrhosis, increased skin pigmentation, diabetes mellitus, etc. Oxidative damage includes - lipid peroxidation - damage to proteins - damage to dna
What is transfusion associated haemosiderosis?
Repeated blood transfusions give gradual accumulation of iron
400ml = 200mg iron
Iron cheating agents such as desferrioxamine can delay but do not stop inevitable effects of iron overload
What is hereditary haemochromatosis?
- autosomal recessive disease caused by mutation in HFE gene
- HFE protein normally interacts with transferrin receptor reducing its affinity for iron bound transferrin
- mutated HFE cant bind to transferrin so negative influence on iron uptake is lost
- too much iron enters cells
- iron accumulates in end organs causing damage
- treat with venesection
